Prostanoids comprise prostaglandins (PGs) and thromboxanes (Txs) and their receptors fall into five different classes (DP, EP, FP, IP and TP) based on their sensitivity to the five naturally occurring prostanoids, PGD2, PGE2, PGF2α, PGI2 and TxA2, respectively (Coleman, R. A., Prostanoid Receptors, IUPHAR compendium of receptor characterisation and classification, 2nd edition, 338-353, ISBN 0-9533510-3-3, 2000). EP receptors (for which the endogenous ligand is PGE2) have been subdivided into four types termed EP1, EP2, EP3 and EP4. These four types of EP receptors have been cloned and are distinct at both a molecular and pharmacological level (Coleman, R. A., 2000)
EP4 antagonists have been shown to be useful in the treatment of pain, and in particular, in the treatment of primary headache disorders, which include migraines, and secondary headache disorders, such as drug-induced headaches (WO 00/18405 and WO 01/72302). Dilation of the cerebral vasculature and the subsequent stimulation of pain stimulating, perivascular trigeminal sensory afferent nerves is recognised to play an important role in the pathophysiology of migraine. A sterile inflammatory response, associated with activation of cycloxygenase and the generation of PGE2, is also implicated in the pathophysiology of migraine. PGE2 levels have been shown to be raised during migraine attacks and PGE2 contributes to the pain of migraine by directly dilating cerebral arteries and by stimulating the release of vasoactive/pro-inflammatory peptides from the trigeminal nerves. These effects of PGE2 are mediated in whole or in part by EP4 receptors. Thus, by binding to and preventing the stimulation of EP4 receptors, EP4 antagonists may be used to treat the pain of migraine.
EP4 antagonists may also be useful in treating a number of other conditions and diseases. For example, they may be used in:
the treatment of pain associated with rheumatoid arthritis, osteoarthritis, rheumatoid spondylitis, gouty arthritis and juvenile arthritis;
the treatment of musculoskeletal pain, lower back and neck pain, sprains and strains, neuropathic pain, sympathetically mediated pain, myositis, pain associated with cancer and fibromyalgia, pain associated with influenza or other viral infections, such as the common cold, rheumatic fever; pain associated with bowel disorders such as non-ulcer dyspepsia, irritable bowel syndrome; non-cardiac chest pain, pain associated with myocardial ischaemia, post-operative pain, headache, toothache and dysmenorrhea. Neuropathic pain syndromes include diabetic neuropathy, sciatica, non-specific lower back pain, multiple sclerosis pain, fibromyalgia, HIV-related neuropathy, post-herpetic neuralgia, trigeminal neuralgia and pain resulting from physical trauma;the treatment of inflammatory diseases including rheumatoid and osteoarthritis, psoriasis, dermatitis, retinitis, conjunctivitis, asthma, bronchitis, chronic obstructive pulmonary disease, inflammatory bowel disease, colitis, nephritis, gingivitis and hepatitis;the treatment of cancers including familial adenomatous polyposis, endometrial carcinoma, colorectal and cervical cancer;the treatment of bone disorders involving altered bone formation or resorption such as osteoporosis;women's health for the treatment of myometrial and endometrial disorders;the treatment of gastrointestinal disease including diarrhea;the treatment of immunological disorders such as autoimmune disease, immunological deficiency diseases, organ transplantation and increasing the latency of HIV infection; the treatment of diseases of abnormal platelet function, (e.g. occlusive vascular diseases);the preparation of a drug with diuretic properties to treat or prevent various oedema, hypertension, premenstrual tension, urinary calculus, oliguria, hyperphosphaturia, mesangial proliferative glomerulonephritis, chronic renal failure or the like;the treatment of impotence or erectile dysfunction, and female sexual dysfunction;the treatment of hair growth disorders;the treatment of sleep disorders such as narcolepsy and insomnia;the treatment of cardiovascular diseases and shock states associated with hypotension (e.g. septic shock);the treatment of neurodegenerative diseases and for preventing neuronal damage following stroke, cardiac arrest, cardiopulmonary bypass, traumatic brain injury or spinal cord injury;the treatment of tinnitus;the treatment of dependence; andthe treatment of complications of diabetes.
Although EP4 antagonists are known, it is desired to find novel EP4 antagonists, and in particular, EP4 antagonists which are selective against other EP receptors, i.e. EP1, EP2 and EP3.